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    Clinical Trial Results:
    A 12-WEEK, MULTICENTER, MULTINATIONAL, RANDOMISED, DOUBLE BLIND, DOUBLE-DUMMY (OPEN LABEL FOR THE SPACER GROUP), 3-ARM PARALLEL GROUP STUDY COMPARING THE EFFICACY AND THE SAFETY OF CHF 1535 HFA pMDI (BDP/FF 100/6 µg per actuation) 2 PUFFS BID VERSUS BDP HFA pMDI (250 µg per actuation) 2 PUFFS BID, IN ADOLESCENT PATIENTS WITH MODERATE TO SEVERE PERSISTENT ASTHMA

    Summary
    EudraCT number
    		 2007-000522-46
    Trial protocol
    		 CZ   HU   PL   SK  
    Global end of trial date
    29 May 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-0606-PR-0019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo, 26/A, Parma, Italy, 43126
    Public contact
    Clinical Trial Transparency Manager, Chiesi Clinical Trials, Chiesi Farmaceutici SpA, ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency Manager, Chiesi Clinical Trials, Chiesi Farmaceutici SpA, ClinicalTrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000548-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 May 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the clinical superiority in terms of pulmonary function (change from baseline in pre-dose morning PEF) of CHF 1535 versus a corresponding dose of beclomethasone monotherapy in adolescent patients with partly controlled moderate to severe persistent asthma over a 12-week treatment period, the two study treatments being administered via a pMDI standard actuator (without spacer).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements . Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Sep 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 45
    Country: Number of subjects enrolled
    Hungary: 47
    Country: Number of subjects enrolled
    Poland: 75
    Country: Number of subjects enrolled
    Russian Federation: 113
    Country: Number of subjects enrolled
    Slovakia: 49
    Country: Number of subjects enrolled
    Ukraine: 119
    Worldwide total number of subjects
    448
    EEA total number of subjects
    216
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    448
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 480 patients were screened; 32 patients failed screening. 448 patients were randomised and 438 patients completed the study.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The study was double blind and double-dummy, but was open label for the spacer group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A - fixed combination BDP/FF pMDI
    Arm description
    		 CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 1535
    Investigational medicinal product code
    Other name
    BDP/FF, beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg)

    Arm title
    		 Treatment B - BDP HFA pMDI
    Arm description
    		 BDP HFA pMDI 250μg (Clenil® 250), 2 inhalations BID (daily dose: 1000 μg BDP)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    BDP HFA pMDI
    Investigational medicinal product code
    Other name
    BDP, bemeclomethasone dipropionate, Clenil® 250
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    BDP HFA pMDI 250μg (Clenil® 250), 2 inhalations BID (daily dose: 1000 μg BDP)

    Arm title
    		 Treatment C - fixed combination BDP/FF by spacer device
    Arm description
    		 CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg) administered by means of spacer device
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 1535 by spacer device
    Investigational medicinal product code
    Other name
    BDP/FF, beclomethasone dipropionate, formoterol fumarate
    Pharmaceutical forms
    Pressurised inhalation, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg) administered by means of spacer device

    Number of subjects in period 1
    		Treatment A - fixed combination BDP/FF pMDI Treatment B - BDP HFA pMDI Treatment C - fixed combination BDP/FF by spacer device
    Started
    150
    148
    150
    Completed
    145
    146
    147
    Not completed
    5
    2
    3
         Consent withdrawn by subject
    1
    1
    -
         unknown
    1
    -
    1
         asthma exacerbation
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    1
         Protocol deviation
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A - fixed combination BDP/FF pMDI
    Reporting group description
    		 CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg).

    Reporting group title
    Treatment B - BDP HFA pMDI
    Reporting group description
    		 BDP HFA pMDI 250μg (Clenil® 250), 2 inhalations BID (daily dose: 1000 μg BDP)

    Reporting group title
    Treatment C - fixed combination BDP/FF by spacer device
    Reporting group description
    		 CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg) administered by means of spacer device

    Reporting group values
    		 Treatment A - fixed combination BDP/FF pMDI Treatment B - BDP HFA pMDI Treatment C - fixed combination BDP/FF by spacer device Total
    Number of subjects
    		 150 148 150 448
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.6 ± 1.73 14.5 ± 1.72 14.4 ± 1.71 -
    Gender categorical
    Units: Subjects
        Female
    		 59 46 51 156
        Male
    		 91 102 99 292
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 57.18 ± 13.63 57.25 ± 14.21 57.68 ± 15.05 -
    Subject analysis sets

    Subject analysis set title
    ITT population - Treatment A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all randomised patients who have received at least one administration of study medication and have at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    ITT population - Treatment B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all randomised patients who have received at least one administration of study medication and have at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    ITT population - Treatment C
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all randomised patients who have received at least one administration of study medication and have at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    safety population - Treatment A
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who will take at least one dose of study medication.

    Subject analysis set title
    safety population - Treatment B
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who will take at least one dose of study medication.

    Subject analysis set title
    Safety population - Treatment C
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who will take at least one dose of study medication.

    Subject analysis sets values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects
    150
    148
    150
    150
    148
    150
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.6 ± 1.73
    14.5 ± 1.72
    14.4 ± 1.71
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    59
    46
    51
        Male
    91
    102
    99
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    57.18 ± 13.63
    57.25 ± 14.21
    57.68 ± 15.05
    ±
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Treatment A - fixed combination BDP/FF pMDI
    Reporting group description
    		 CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg).

    Reporting group title
    Treatment B - BDP HFA pMDI
    Reporting group description
    		 BDP HFA pMDI 250μg (Clenil® 250), 2 inhalations BID (daily dose: 1000 μg BDP)

    Reporting group title
    Treatment C - fixed combination BDP/FF by spacer device
    Reporting group description
    		 CHF 1535, 2 inhalations BID (daily dose: BDP 400 μg / formoterol fumarate 24 μg) administered by means of spacer device

    Subject analysis set title
    ITT population - Treatment A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all randomised patients who have received at least one administration of study medication and have at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    ITT population - Treatment B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all randomised patients who have received at least one administration of study medication and have at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    ITT population - Treatment C
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all randomised patients who have received at least one administration of study medication and have at least one available evaluation of efficacy after baseline.

    Subject analysis set title
    safety population - Treatment A
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who will take at least one dose of study medication.

    Subject analysis set title
    safety population - Treatment B
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who will take at least one dose of study medication.

    Subject analysis set title
    Safety population - Treatment C
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who will take at least one dose of study medication.

    Primary: Change from baseline in pre-dose morning PEF

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    End point title
    		 Change from baseline in pre-dose morning PEF
    End point description
    Change from baseline in pre-dose morning PEF (L/min) [the mean of the last 7 available values during the run-in period and during the last 14 days of the treatment period will be considered].
    End point type
    Primary
    End point timeframe
    Daily at home via SpirotelTM from Visit 1 to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    64
    52
    64
    Units: L/min
        arithmetic mean (standard deviation)
    13.12 ± 45.826
    19.35 ± 58.997
    36.17 ± 48.328
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The primary analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator). To demonstrate the superiority of CHF 1535 vs BDP monotherapy, the primary endpoint (change from baseline in pre-dose morning PEF) has been submitted to an analysis of covariance (ANCOVA) model, using the baseline as covariate and treatment and country as factors. This particular comparison is about Treatment B vs Treatment A
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.45
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    7.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.74
         upper limit
    		 26.33

    Secondary: Pre-dose evening PEF

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    End point title
    		 Pre-dose evening PEF
    End point description
    Pre-dose evening PEF measured with the electronic peak flow meter in the last 14 days before each clinic visit. Only changes from baseline to treatment phase are reported here. Entire treatment phase is the mean of all available values during the treatment period.
    End point type
    Secondary
    End point timeframe
    Daily at home via SpirotelTM from Visit 1 to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    130
    132
    124
    Units: L/min
        arithmetic mean (standard deviation)
    10.85 ± 41.715
    3.97 ± 43.654
    22.3 ± 38.707
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.223
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -6.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.12
         upper limit
    		 3.78
    Notes
    [1] - The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).

    Secondary: Daily PEF variability

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    End point title
    		 Daily PEF variability
    End point description
    For daily PEF variability the mean of the last seven available values during the run-in period was used as baseline and the mean of the last seven available values during the last 14 days before Visits 3, 4 and 5, respectively was to be used as post-baseline measurements. Only changes from baseline to treatment phase are reported here. Entire treatment phase is the mean of all available values during the treatment period.
    End point type
    Secondary
    End point timeframe
    Daily PEF variability from baseline to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    127
    126
    118
    Units: L/min
        arithmetic mean (standard deviation)
    -1.05 ± 7.772
    -0.95 ± 7.765
    -2 ± 6.605
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.874
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 1.43

    Secondary: Pre-dose FEV1

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    End point title
    		 Pre-dose FEV1
    End point description
    Only changes from baseline to treatment phase are reported here. Entire treatment phase is the mean of all available values during the treatment period.
    End point type
    Secondary
    End point timeframe
    At each clinic visit from Visit 2 to Visit 5.
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    148
    146
    150
    Units: liter
        arithmetic mean (standard deviation)
    0.37 ± 0.408
    0.34 ± 0.414
    0.43 ± 0.466
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.376
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.05

    Secondary: Post-dose FEV1

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    End point title
    		 Post-dose FEV1
    End point description
    Post-dose FEV1 at 10 min, 30 min, 1 hour at each clinic visit and relative 1h average (i.e. 1h AUC standardised by time). Only absolute post-dose FEV1 AUC1hstd at Visit 5 is reported here.
    End point type
    Secondary
    End point timeframe
    At each clinic visit from Visit 2 to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    145
    146
    147
    Units: liter
        arithmetic mean (standard deviation)
    3.207 ± 0.7347
    3.066 ± 0.7772
    3.212 ± 0.802
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.012
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.241
         upper limit
    		 -0.029

    Secondary: Pre-dose FVC

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    End point title
    		 Pre-dose FVC
    End point description
    Only changes in pre-dose FVC from baseline at Visit 5 are reported here.
    End point type
    Secondary
    End point timeframe
    At each clinic visit from Visit 2 to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    146
    146
    148
    Units: liter
        arithmetic mean (standard deviation)
    0.41 ± 0.516
    0.45 ± 0.555
    0.43 ± 0.536
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.555
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.15

    Secondary: Post-dose FVC

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    End point title
    		 Post-dose FVC
    End point description
    Post-dose FVC at 10 min, 30 min, 1 hour at each clinic visit. Only changes in post-dose FVC from baseline 1 hour after at Visit 5 are reported here.
    End point type
    Secondary
    End point timeframe
    At each clinic visit from visit 2 to visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    145
    146
    147
    Units: liter
        arithmetic mean (standard deviation)
    0.57 ± 0.535
    0.59 ± 0.593
    0.59 ± 0.556
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.757
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.14

    Secondary: Pre-dose FEF25-75%

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    End point title
    		 Pre-dose FEF25-75%
    End point description
    Only changes in pre-dose FEF25-75% from baseline at Visit 5 are reported here.
    End point type
    Secondary
    End point timeframe
    At each clinic visit from Visit 2 to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    145
    146
    148
    Units: L/sec
        arithmetic mean (standard deviation)
    0.51 ± 0.836
    0.38 ± 0.823
    0.58 ± 0.973
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment B v ITT population - Treatment A
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.104
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.03

    Secondary: Post-dose FEF25-75%

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    End point title
    		 Post-dose FEF25-75%
    End point description
    Post-dose FEF25-75% at 10 min, 30 min, 1 hour at each clinic visit and relative 1h average (i.e. 1h AUC standardised by time). Only changes in post-dose FEF25-75% from baseline 1 hour after at Visit 5 are reported here.
    End point type
    Secondary
    End point timeframe
    at each clinic visit from Visit 2 to Visit 5
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    144
    146
    147
    Units: L/min
        arithmetic mean (standard deviation)
    1.01 ± 0.905
    0.54 ± 0.906
    1.07 ± 1.033
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.29

    Secondary: Total morning asthma symptom score

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    End point title
    		 Total morning asthma symptom score
    End point description
    For the total asthma symptom scores the mean of the last seven available values during the run-in period were to be used as baseline and the mean of the last seven available values during the last 14 days before Visits 3, 4 and 5, respectively were to be used as post-baseline measurements. Only change in total morning (night time symptoms) asthma symptom scores from baseline to “end of treatment” are reported here.
    End point type
    Secondary
    End point timeframe
    Each day throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    138
    130
    139
    Units: integer
        arithmetic mean (standard deviation)
    -0.76 ± 1.82
    -0.51 ± 1.586
    -0.33 ± 1.87
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.436
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.53

    Secondary: Total evening asthma symptom score

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    End point title
    		 Total evening asthma symptom score
    End point description
    For the total asthma symptom scores the mean of the last seven available values during the run-in period were to be used as baseline and the mean of the last seven available values during the last 14 days before Visits 3, 4 and 5, respectively were to be used as post-baseline measurements. Only change in total evening (day time symptoms) symptom scores from baseline to “end of treatment” are reported here.
    End point type
    Secondary
    End point timeframe
    Each day throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    137
    129
    135
    Units: integer
        arithmetic mean (standard deviation)
    -0.93 ± 2.037
    -0.72 ± 1.662
    -0.59 ± 2.066
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.485
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.56

    Secondary: Total all day asthma symptom score

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    End point title
    		 Total all day asthma symptom score
    End point description
    For the total asthma symptom scores the mean of the last seven available values during the run-in period were to be used as baseline and the mean of the last seven available values during the last 14 days before Visits 3, 4 and 5, respectively were to be used as post-baseline measurements. Only change in total all day asthma symptom scores from baseline to “end of treatment” are reported here.
    End point type
    Secondary
    End point timeframe
    Each day throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    125
    120
    127
    Units: integer
        arithmetic mean (standard deviation)
    -1.67 ± 3.765
    -1.12 ± 2.924
    -0.91 ± 3.867
    Statistical analysis title
    		 Comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.293
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 1.25

    Secondary: Symptom-free days

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    End point title
    		 Symptom-free days
    End point description
    Symptom free days were defined as days with a daily evening total asthma score of 0. For symptom free days, nights and complete days, the sum of all symptom free days, nights and complete days, respectively during the run-in period were to be used as baseline and the sum of symptom free days, nights and complete days, respectively during the entire treatment period were to be used as post-baseline measurement. The percentage of symptom free days, nights and complete days were computed as follows: Sum of symptom free days, nights or complete days, respectively during a measurement period (baseline, post-baseline, respectively) divided by the duration (days) of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    149
    144
    148
    Units: percentage
        arithmetic mean (standard deviation)
    17.36 ± 31.021
    23.89 ± 29.268
    19.27 ± 33.714
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.089
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    5.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 12.12

    Secondary: Symptom-free nights

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    End point title
    		 Symptom-free nights
    End point description
    Symptom free nights were defined as nights with a daily morning total asthma score of 0.For symptom free days, nights and complete days, the sum of all symptom free days, nights and complete days, respectively during the run-in period were to be used as baseline and the sum of symptom free days, nights and complete days, respectively during the entire treatment period were to be used as post-baseline measurement. The percentage of symptom free days, nights and complete days were computed as follows: Sum of symptom free days, nights or complete days, respectively during a measurement period (baseline, post-baseline, respectively) divided by the duration (days) of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    150
    145
    149
    Units: percentage
        arithmetic mean (standard deviation)
    14.66 ± 34.175
    14.63 ± 29.866
    16.89 ± 31.348
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.635
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.96
         upper limit
    		 8.12

    Secondary: Symptom-free days and nights (complete day)

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    End point title
    		 Symptom-free days and nights (complete day)
    End point description
    Symptom free days and nights (complete days) were defined as days with a daily all day asthma score of 0.For symptom free days, nights and complete days, the sum of all symptom free days, nights and complete days, respectively during the run-in period were to be used as baseline and the sum of symptom free days, nights and complete days, respectively during the entire treatment period were to be used as post-baseline measurement. The percentage of symptom free days, nights and complete days were computed as follows: Sum of symptom free days, nights or complete days, respectively during a measurement period (baseline, post-baseline, respectively) divided by the duration (days) of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    148
    143
    148
    Units: percentage
        arithmetic mean (standard deviation)
    19.65 ± 32.423
    23.78 ± 29.839
    21.48 ± 34.73
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.207
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    4.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.45
         upper limit
    		 11.26

    Secondary: Day use of rescue salbutamol

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    End point title
    		 Day use of rescue salbutamol
    End point description
    The sum of all days with day, night or day and night salbutamol usage, respectively during the run-in period was to be used as baseline and the sum of all days with day, night or day and night salbutamol usage, respectively during the entire treatment period was to be used as post-baseline measurement. The percentage of rescue salbutamol usage days was computed as follows: Sum of all days with day, night, day and night and any rescue medication during a measurement period (baseline, post-baseline, respectively) divided by the duration [days] of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Each day throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    149
    144
    148
    Units: percentage
        arithmetic mean (standard deviation)
    -13.38 ± 25.538
    -8.71 ± 22.319
    -13.68 ± 27.489
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.133
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.96
         upper limit
    		 7.18
    Notes
    [2] - Change in use of rescue salbutamol (absolute and relative) from baseline is reported here

    Secondary: Night use of rescue salbutamol

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    End point title
    		 Night use of rescue salbutamol
    End point description
    The sum of all days with day, night or day and night salbutamol usage, respectively during the run-in period was to be used as baseline and the sum of all days with day, night or day and night salbutamol usage, respectively during the entire treatment period was to be used as post-baseline measurement. The percentage of rescue salbutamol usage days was computed as follows: Sum of all days with day, night, day and night and any rescue medication during a measurement period (baseline, post-baseline, respectively) divided by the duration [days] of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Each day throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    150
    145
    149
    Units: percentage
        arithmetic mean (standard deviation)
    -10.62 ± 24.789
    -7.05 ± 21.813
    -10.85 ± 24.73
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.213
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 6.6
    Notes
    [3] - Change in use of rescue salbutamol (absolute and relative) from baseline is reported here

    Secondary: Day or night use of rescue salbutamol

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    End point title
    		 Day or night use of rescue salbutamol
    End point description
    The sum of all days with day, night or day and night salbutamol usage, respectively during the run-in period was to be used as baseline and the sum of all days with day, night or day and night salbutamol usage, respectively during the entire treatment period was to be used as post-baseline measurement. The percentage of rescue salbutamol usage days was computed as follows: Sum of all days with day, night, day and night and any rescue medication during a measurement period (baseline, post-baseline, respectively) divided by the duration [days] of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Each day throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    148
    143
    148
    Units: percentage
        arithmetic mean (standard deviation)
    -15.46 ± 29.572
    -10.96 ± 26.18
    -16.9 ± 29.68
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.288
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 7.31
    Notes
    [4] - Change in use of rescue salbutamol (absolute and relative) from baseline is reported here

    Secondary: Asthma control days

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    End point title
    		 Asthma control days
    End point description
    An asthma control day was defined as: An all day total asthma symptom score of 0 and all day without usage of rescue medication. For the asthma control days the sum of all asthma control days during the run-in period was to be used as baseline and the sum of all asthma control days during the entire treatment period was to be used as post-baseline measurement. The percentage of asthma control days was computed as follows: Sum of asthma control days during a measurement period (baseline, post-baseline, respectively) divided by the duration [days] of the respective measurement period multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Throughout the run-in period and the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    148
    143
    148
    Units: percentage
        arithmetic mean (standard deviation)
    20.44 ± 33.034
    24.34 ± 30.121
    22.54 ± 35.165
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator)
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.28
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.11
         upper limit
    		 10.71
    Notes
    [5] - Change in asthma control days (absolute and relative) from baseline is reported here

    Secondary: Moderate/severe asthma exacerbations

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    End point title
    		 Moderate/severe asthma exacerbations
    End point description
    The total number of moderate/severe asthma exacerbations and the number of patients with moderate/severe asthma exacerbation during the treatment phase were evaluated
    End point type
    Secondary
    End point timeframe
    Throughout the treatment period
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    150
    148
    150
    Units: number of subjects
    3
    1
    0
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment B v ITT population - Treatment A
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.622
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of patients achieving the level of "controlled" asthma

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    End point title
    		 Proportion of patients achieving the level of "controlled" asthma
    End point description
    Asthma control was evaluated based on the relevant measurements for assessing asthma control recorded CRF and Spirotel™. An assessment of asthma control was performed during the run-in period and during the last 14 days of treatment, according to the criteria defined by GINA Guidelines revised 2006.
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 ITT population - Treatment A ITT population - Treatment B ITT population - Treatment C
    Number of subjects analysed
    150
    148
    150
    Units: number of subject
    46
    45
    62
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    ITT population - Treatment A v ITT population - Treatment B
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.999 [6]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [6] - p values are from Fisher's exact test comparing proportion of patients between groups

    Secondary: Overnight 12-h urinary cortisol/creatinine ratios

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    End point title
    		 Overnight 12-h urinary cortisol/creatinine ratios
    End point description
    Only data at Visit 5 are reported here. Data are from 50% of all randomized patients
    End point type
    Secondary
    End point timeframe
    At Visit 2 and at Visit 5, in a subset of 50% of each group of patients
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    62
    63
    62
    Units: μmol/mol
        arithmetic mean (standard deviation)
    33.1 ± 28.66
    25.7 ± 23.77
    28.1 ± 19.7
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    safety population - Treatment A v safety population - Treatment B
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.103
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.2
         upper limit
    		 1.3

    Secondary: Morning serum cortisol

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    End point title
    		 Morning serum cortisol
    End point description
    Only data at Visit 5 are reported here
    End point type
    Secondary
    End point timeframe
    At Visit 2 and at Visit 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    146
    145
    149
    Units: nmol/L
        arithmetic mean (standard deviation)
    384.8 ± 152.112
    339.82 ± 163.236
    361.28 ± 139.476
    Statistical analysis title
    		 comparison between treatments (B vs A)
    Statistical analysis description
    The analysis is the comparison between CHF 1535 and BDP monotherapy (both administered via a pMDI standard actuator).
    Comparison groups
    safety population - Treatment A v safety population - Treatment B
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.041
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64.84
         upper limit
    		 -1.24

    Secondary: Blood glucose

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    End point title
    		 Blood glucose
    End point description
    Only data at Visit 5 are reported here
    End point type
    Secondary
    End point timeframe
    At Visit 2 and at Visit 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    145
    146
    149
    Units: mmol/L
        arithmetic mean (standard deviation)
    5.01 ± 0.65
    4.97 ± 0.453
    4.99 ± 0.489
    No statistical analyses for this end point

    Secondary: Serum potassium

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    End point title
    		 Serum potassium
    End point description
    End point type
    Secondary
    End point timeframe
    At Visit 2 and at Visit 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    145
    146
    149
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.38 ± 0.412
    4.43 ± 0.43
    4.37 ± 0.387
    No statistical analyses for this end point

    Secondary: Heart rate

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    End point title
    		 Heart rate
    End point description
    Only post-dose change from baseline in HR, at visit 5, is reported here.
    End point type
    Secondary
    End point timeframe
    At Visits 1, 2, 3, 4, 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    145
    146
    147
    Units: bpm
        arithmetic mean (standard deviation)
    -1.8 ± 11.21
    -2.4 ± 9.21
    -1.1 ± 10.64
    No statistical analyses for this end point

    Secondary: Systolic blood pressure

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    End point title
    		 Systolic blood pressure
    End point description
    Only post-dose change from baseline in SBP, at visit 5, is reported here.
    End point type
    Secondary
    End point timeframe
    At each Visit
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    145
    146
    147
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.2 ± 7.87
    0.7 ± 9.13
    1.3 ± 8.29
    No statistical analyses for this end point

    Secondary: Diastolic blood pressure

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    End point title
    		 Diastolic blood pressure
    End point description
    Only post-dose change from baseline in DBP, at visit 5, is reported here.
    End point type
    Secondary
    End point timeframe
    At each Visit
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    145
    146
    147
    Units: mmHg
        arithmetic mean (standard deviation)
    0.1 ± 7.65
    0.4 ± 7.51
    0.3 ± 7.59
    No statistical analyses for this end point

    Secondary: QT interval by Bazett's

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    End point title
    		 QT interval by Bazett's
    End point description
    Only data 30 min post-dose at Visit 5 corrected by Bazett's formula are reported here
    End point type
    Secondary
    End point timeframe
    pre-dose and 30 min post dose at Visit 2 and Visit 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    144
    143
    146
    Units: msec
        arithmetic mean (standard deviation)
    413.3 ± 19.93
    404.5 ± 20.16
    412 ± 20.18
    No statistical analyses for this end point

    Secondary: QT interval by Fridericia

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    End point title
    		 QT interval by Fridericia
    End point description
    Only data 30 post-dose at Visit 5 corrected by Fridericia formula are reported here
    End point type
    Secondary
    End point timeframe
    Pre-dose and 30 min post-dose at Visit 2 and at Vist 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    144
    143
    146
    Units: msec
        arithmetic mean (standard deviation)
    404.3 ± 15.61
    400.8 ± 15.34
    402.9 ± 15.85
    No statistical analyses for this end point

    Secondary: Standard haematology - Hematocrit

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    End point title
    		 Standard haematology - Hematocrit
    End point description
    Only data on Hematocrit at Visit 5 on safety population are reported here. All the other haematologic parameters (red cell count, white cell count, neutrophils, Total lymphocìytes, monocytes, eosinophils, basophils, neutrophils, platelets, hemoglobin) on safety population are comprised and tabulated in the study's results but are not reported here.
    End point type
    Secondary
    End point timeframe
    At Visits 1 and 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    138
    140
    143
    Units: L/L
        arithmetic mean (standard deviation)
    0.42 ± 0.031
    0.426 ± 0.034
    0.418 ± 0.033
    No statistical analyses for this end point

    Secondary: Standard biochemistry - sodium

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    End point title
    		 Standard biochemistry - sodium
    End point description
    Only sodium levels on Visit 5 are reported here. All the other biochemical parameters (chloride, urea, Creatinine, bilirubin, AST, ALT, GGT, AP, calcium, PHO, cholesterol, triglycerides, CRP) on safety population are comprised and tabulated in the study's results but are not reported here.
    End point type
    Secondary
    End point timeframe
    At Visits 1 and 5
    End point values
    		 safety population - Treatment A safety population - Treatment B Safety population - Treatment C
    Number of subjects analysed
    146
    146
    149
    Units: mmol/l
        arithmetic mean (standard deviation)
    140 ± 1.68
    140.1 ± 1.65
    140 ± 1.61
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Visit 2 to Visit 5 (treatment period)
    Adverse event reporting additional description
    All adverse events, either reported by the patient, or observed by the Investigator, were recorded in source notes and transcribed into the CRF. The patient was also questioned about any adverse event(s) at each visit. Analysis of safety variables was performed in the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Analysis of safety variables was performed in the safety population. The safety population included all randomised patients who took at least one dose of study medication.

    Reporting group title
    Treatment B
    Reporting group description
    		 Analysis of safety variables was performed in the safety population. The safety population included all randomised patients who took at least one dose of study medication.

    Reporting group title
    Treatment C
    Reporting group description
    		 Analysis of safety variables was performed in the safety population. The safety population included all randomised patients who took at least one dose of study medication.

    Serious adverse events
    		 Treatment A Treatment B Treatment C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 150 (2.00%)
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Mild abdominal pain due to alimentary reason
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
    Additional description: Mild anal haemorrhoids
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 148 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma exacerbation
    Additional description: Moderate asthma exacerbation
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 148 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 148 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute respiratory viral infection
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 148 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Treatment A Treatment B Treatment C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 150 (28.67%)
    43 / 148 (29.05%)
    51 / 150 (34.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 150 (2.67%)
    3 / 148 (2.03%)
    2 / 150 (1.33%)
         occurrences all number
    4
    7
    2
    Tremor
         subjects affected / exposed
    2 / 150 (1.33%)
    1 / 148 (0.68%)
    3 / 150 (2.00%)
         occurrences all number
    2
    1
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 150 (0.67%)
    2 / 148 (1.35%)
    3 / 150 (2.00%)
         occurrences all number
    1
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 150 (2.67%)
    2 / 148 (1.35%)
    2 / 150 (1.33%)
         occurrences all number
    4
    3
    2
    Cough
         subjects affected / exposed
    3 / 150 (2.00%)
    3 / 148 (2.03%)
    1 / 150 (0.67%)
         occurrences all number
    3
    3
    2
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    8 / 150 (5.33%)
    8 / 148 (5.41%)
    7 / 150 (4.67%)
         occurrences all number
    8
    8
    7
    Nasopharyngitis
         subjects affected / exposed
    8 / 150 (5.33%)
    7 / 148 (4.73%)
    7 / 150 (4.67%)
         occurrences all number
    8
    8
    7
    Respiratory tract infection viral
         subjects affected / exposed
    6 / 150 (4.00%)
    3 / 148 (2.03%)
    7 / 150 (4.67%)
         occurrences all number
    7
    4
    7
    Respiratory tract infection
         subjects affected / exposed
    5 / 150 (3.33%)
    6 / 148 (4.05%)
    5 / 150 (3.33%)
         occurrences all number
    5
    7
    5
    Bronchitis
         subjects affected / exposed
    4 / 150 (2.67%)
    5 / 148 (3.38%)
    6 / 150 (4.00%)
         occurrences all number
    4
    5
    6
    Rhinitis
         subjects affected / exposed
    1 / 150 (0.67%)
    2 / 148 (1.35%)
    6 / 150 (4.00%)
         occurrences all number
    1
    2
    7
    Acute tonsillitis
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 148 (0.68%)
    3 / 150 (2.00%)
         occurrences all number
    1
    1
    3
    Oral candidiasis
         subjects affected / exposed
    1 / 150 (0.67%)
    3 / 148 (2.03%)
    0 / 150 (0.00%)
         occurrences all number
    1
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No limitations or caveats are applicable to this summary of results
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